Most patients with pancreatic cancer present with advanced incurable disease, but patients diagnosed with Stage I pancreatic cancer have a much better outcome. The early detection of pancreatic cancer requires simple and effective pancreatic screening tests that can be applied to high risk populations. The Cancer of the Pancreas Screening (CAPS) study currently follows a familial/genetic ?high-risk? cohort of ~1000 patients undergo regular pancreatic surveillance. Recent results from the CAPS program indicate that pancreatic cancers detected during pancreatic surveillance are down-staged; 40% of those who maintained annual surveillance had a Stage I pancreatic cancer. These results indicate that early detection can improve overall outcome of patients with pancreatic cancer. Circulating tumor marker tests are not currently used for pancreas surveillance. Genetic factors are known to influence tumor marker levels, but gene tests have not been evaluated to determine if they could improve the accuracy of tumor markers. Recent studies from the PI's lab indicate that the normal reference ranges of commonly used tumor markers (CA19-9, CA-125 and CEA) are better defined by an individual's tumor marker genotype. A tumor marker genotype test can improve the diagnostic sensitivity of tumor markers at 99% specificity compared to conventional diagnostic cut-offs. We propose to establish genetically-defined normal reference ranges for tumor marker levels and evaluate their diagnostic accuracy in a prospective clinical trial of patients undergoing pancreatic imaging surveillance through our CAPS program. The addition of annual blood tests to pancreatic surveillance is expected to improve the detection of early-stage pancreatic cancer.